title: Possible involvement of CCL1-CCR8 interaction in lymphocytic recruitment in IgG4-related sclerosing cholangitis.
abstract: OBJECTIVE
  IgG4-related sclerosing cholangitis and type 1 autoimmune pancreatitis (IgG4-SC/AIP) are characterized by massive lymphoplasmacytic infiltration including Th2 and regulatory T cells (Tregs). This study was conducted to address which chemotactic factors are involved in this condition.
  
  
  METHODS
  Chemokine expression profiles in tissue were examined in IgG4-SC/AIP (n=17), classical primary sclerosing cholangitis (IgG4(low) PSC, n=17), PSC with elevated serum/tissue IgG4 levels (IgG4(high) PSC, n=5), and primary biliary cirrhosis (n=7). We focused on five chemotactic factors/receptors (CCL1-CCR8, CCL17/CCL22-CCR4), given that CCR4 and CCR8 are predominantly expressed in both Th2 and Tregs.
  
  
  RESULTS
  In conjunction with higher expression levels of IL-4 and IL-10, expression values of CCL1 and CCR8 transcripts were significantly higher in IgG4-SC/AIP than in IgG4(low) PSC (p=0.002) and IgG4(high) PSC (p=0.023). CCL1 and CCR8 were also overexpressed in IgG4(high) PSC than in IgG4(low) PSC (p=0.023). No difference was seen for CCL17, CCL22, and CCR4. In situ hybridization revealed CCL1 to be predominantly expressed in the pancreatic duct epithelium, peribiliary glands, and vascular endothelial cells including the ones involved in obliterative phlebitis in IgG4-SC/AIP, in contrast to IgG4(high) PSC where this chemotactic factor was positive in several infiltrating lymphocytes. These CCL1-expressing sites were infiltrated by CCR8(+) lymphocytes. On immunohistochemistry, GATA3(+) Th2 lymphocytes and FOXP3(+) Tregs were significantly larger in number in IgG4-SC/AIP, with the GATA3(+)/T-bet(+) cell ratio to be shifted in favour of Th2 in periductal and perivascular areas.
  
  
  CONCLUSIONS
  CCL1-CCR8 interaction may play a critical role in lymphocytic recruitment in IgG4-SC/AIP, leading to duct-centred inflammation and obliterative phlebitis.
authors.affiliation: Institute of Liver Studies, King's College London at King's College Hospital, London, UK. Electronic address: yoh.zen@kcl.ac.uk.
authors.forename: Yoh
authors.initials: Y
authors.lastname: Zen
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Liberal
authors.forename: Yasuni
authors.initials: Y
authors.lastname: Nakanuma
authors.forename: Nigel
authors.initials: N
authors.lastname: Heaton
authors.forename: Bernard
authors.initials: B
authors.lastname: Portmann
mesh_terms: D000328:Adult; D000368:Aged; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology; D054402:Chemokine CCL1 / Q000502:physiology*; D054414:Chemokine CCL17 / Q000378:metabolism; D054422:Chemokine CCL22 / Q000378:metabolism; D015209:Cholangitis, Sclerosing / Q000276:immunology* / Q000473:pathology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D050990:GATA3 Transcription Factor / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000502:physiology*; D016753:Interleukin-10 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010195:Pancreatitis / Q000276:immunology / Q000473:pathology; D054398:Receptors, CCR4 / Q000378:metabolism; D054401:Receptors, CCR8 / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*
chemical_list: C065971:CCL1 protein, human; C106230:CCL17 protein, human; C515482:CCL22 protein, human; C515354:CCR4 protein, human; C103330:CCR8 protein, human; D054402:Chemokine CCL1; D054414:Chemokine CCL17; D054422:Chemokine CCL22; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D007074:Immunoglobulin G; D054398:Receptors, CCR4; D054401:Receptors, CCR8; D016753:Interleukin-10; D015847:Interleukin-4
keywords: Autoimmune pancreatitis; Chemokine; Cytokine; IgG4; IgG4(high) PSC; IgG4(low) PSC; IgG4-SC/AIP; IgG4-related sclerosing cholangitis and type 1 autoimmune pancreatitis; Obliterative phlebitis; PBC; PSC; Primary sclerosing cholangitis; Regulatory T cell; Th2; Treg; high-power field; hpf; primary biliary cirrhosis; primary sclerosing cholangitis; primary sclerosing cholangitis with elevated IgG4; primary sclerosing cholangitis with normal IgG4; regulatory T cell